CN102138914B - film-form preparation - Google Patents
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- CN102138914B CN102138914B CN201110030217.3A CN201110030217A CN102138914B CN 102138914 B CN102138914 B CN 102138914B CN 201110030217 A CN201110030217 A CN 201110030217A CN 102138914 B CN102138914 B CN 102138914B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/35—Allergens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/08—Antiallergic agents
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Abstract
The invention provides the manufacture method of film-form preparation and this film-form preparation, according to this film-form preparation, in desensitization therapy, patient oneself can give allergen and adjust dosage, and Portability is also excellent, without dregs sense, mis-taking preventive is also excellent, nursing staff is easily administered, it is possible to the QOL of patient and nursing staff is greatly improved, in addition, can at random control in oral cavity, the dissolution time in especially Sublingual, meanwhile, it is capable to lower intraoral sticky sense, improve sense of touch when touch.This film-form preparation contains one or more the granule in the sugar selecting free monosaccharide～six sugar of allergen, edible polymer solvable in water and polar organic solvent and mean diameter 0.1～100 μm and the group of their sugar alcohol composition.
Description
Technical field
The present invention relates to and can hold diffluent film-form preparation in oral cavity.More specifically, the present invention relates to a kind of film-form preparation, it is suitable for the per os for the purpose of specific desensitization therapy or sublingual administration, described specific desensitization therapy by being exposed in the oral cavity of patient (such as oral mucosa by allergen within the time of regulation, especially in hypoglossis mucous membrane) and give this allergen, so that the tolerance of patient's adaptive immune.
Background technology
As the treatment for anaphylactic diseases such as pollen hypersensitivities, substantially using the symptomatic therapy of antihistaminic at present, in recent years, as the Therapeutic Method that can effect a radical cure anaphylactic disease, desensitization therapy is noticeable.
Due to desensitization therapy it is generally required to the long-time administration of about 2～3 years, it is taken as that be required to improve further the dosage form of the QOL (quality of life) of nursing staff and patient.
At present, as the dosage form for specific desensitization therapy, the injection for the purpose of subcutaneous injection substantially.
But, based in hypodermic specific desensitization therapy, there is problems of the danger of anaphylactic shock, must be administered by medical personnel, need frequently to go to a hospital to see a doctor in long-time, inject bring pain, need cold preservation keeping etc..
To this, in recent years, America and Europe, liquor and tablet for the purpose of sublingual administration are commercially sold, and it is noticeable due to few side effects and simplicity.
But, in the specific desensitization therapy utilizing the sublingual administration of liquor to carry out, have that dosage is inaccurate, need the problems such as cold preservation keeping.
On the other hand, as solid preparations such as the tablets containing allergen, for instance, it is proposed that containing oxygen metal salt and antigen and selected from the solid vaccine (patent documentation 1) of saccharide, sugar alcohol, aminoacid or its pharmaceutically lyophilization thing in admissible salt；Fast dispersibility non-compacted solid dosage form (patent documentation 2) etc. containing substrate and at least one allergen.
But, utilize in the specific desensitization therapy that the sublingual administration of tablet carries out, exist wrongly take, dosage adjustment is difficult, Portability is poor, dregs are to problems such as the senses of discomfort brought in oral cavity.
Accordingly, as the method dealing with this problem, it is contemplated that in oral cavity, the thin film formulations of display and dissolubility can as a selection scheme.
As the film-form preparation containing allergen, it is currently known and allergen isoreactivity material is dispersed or dissolved in the preparation obtained in water-soluble polymer, it has for instance been proposed that: not self-coagulation and the uniform film product showing heterogeneity and preparation method thereof (patent documentation 3)；Including at least one water-soluble polymer and without the rapid dissolution film article of plasticizer, wherein, water-soluble polymer can only include polyoxyethylene or combination containing polyoxyethylene and hydrophilic cellulosic polymers (patent documentation 4)；The active delivery edible film (patent documentation 5) etc. with self-supporting containing edibility water-soluble polymer, antitack agent and active substance.
For this film-form preparation containing allergen, it is desirable to lower sticky sense when applying in oral cavity and sticky feeling when touch.
As the method lowering sticky sense or sticky feeling, for instance the known method coordinating non-reducing sugar or sugar alcohol in film-form preparation, relate in the film-form preparation of allergen at present, reported the preparation coordinating non-reducing sugar and sugar alcohol.
But, current film-form preparation is to be dispersed or dissolved in water-soluble polymer by allergen isoreactivity material, so the solvent in its manufacture process uses water or its mixed liquor, the sugar of cooperation and sugar alcohol to be in the state of dissolving or recrystallization in the film-form preparation manufactured.
Therefore, in current film-form preparation, by adding sugar and sugar alcohol, especially only add substantial amounts of sugar and sugar alcohol, it is impossible to fully meet the thin film physical property of sticky sense when applying in oral cavity, sticky feeling when touch and such as high film strength etc.Additionally, due to be difficult to arbitrarily control intraoral dissolution time, therefore can not be called and be most suitable for utilizing allergen that patient is carried out the preparation of desensitization therapy.
Prior art literature
Patent documentation
Patent documentation 1: Japanese Unexamined Patent Application Publication 2009-510136 publication
Patent documentation 2: Japanese Unexamined Patent Application Publication 2006-513269 publication
Patent documentation 3: Japanese Unexamined Patent Application Publication 2005-511522 publication
Patent documentation 4: Japanese Unexamined Patent Application Publication 2007-500252 publication
Patent documentation 5: Japanese Unexamined Patent Application Publication 2009-507854 publication
Summary of the invention
The problem that invention to solve
In view of above-mentioned present situation, it is an object of the invention to provide the manufacture method of film-form preparation and this film-form preparation, described film-form preparation is in desensitization therapy, patient oneself can give allergen and adjust dosage, Portability is also excellent, sense without dregs, mis-taking preventive is also excellent, nursing staff is easily administered, the QOL of patient and nursing staff can be greatly improved, in addition, can at random control in oral cavity, especially the dissolution time in Sublingual, simultaneously, intraoral sticky sense can be lowered, and sticky feeling (raising sense of touch) when touch can be lowered, it is obtained in that high film strength.
For solving the scheme of problem
The present inventor etc. are in order to solve above-mentioned problem, conduct in-depth research, it was found that use water-soluble polymer also solvable in organic solvent so that sugar and sugar alcohol are with microgranular scattered film-form preparation, its characteristic significantly improves compared with conventional product, thus completing the present invention.
Namely, the present invention is a kind of film-form preparation, and it contains one or more the granule in the sugar of free monosaccharide～six sugar of choosing and the group of their sugar alcohol composition that allergen, edible polymer solvable in water and polar organic solvent and mean diameter are 0.1～100 μm.
In the film-form preparation of the present invention, the mean diameter of the sugar of above-mentioned monosaccharide～six sugar or the granule of their sugar alcohol is preferably 0.1～30 μm.
It addition, the sugar of above-mentioned monosaccharide～six sugar is preferably non-reducing sugar.
It addition, above-mentioned edible polymer solvable in water and polar organic solvent is preferably polyvinyl pyrrolidone and/or hydroxypropyl cellulose.
In the film-form preparation of the present invention, the molecular weight of above-mentioned polyvinyl pyrrolidone is preferably 2500～3,000,000.
It addition, the molecular weight of hydroxypropyl cellulose is preferably 10,000～1,200,000.
Additionally, the present invention is the manufacture method of a kind of film-form preparation, described film-form preparation contains allergen, edible polymer solvable in water and polar organic solvent and mean diameter are one or more the granule in the sugar selecting free monosaccharide～six sugar of 0.1～100 μm and the group of their sugar alcohol composition, this manufacture method includes: by above-mentioned edible polymer solvable in water and polar organic solvent, the sugar selecting free monosaccharide～six sugar that mean diameter is 0.1～100 μm adds, with one or more the granule in the group of their sugar alcohol composition and above-mentioned allergen, the operation preparing particle dispersion in polar organic solvent to；Form the thin layer of above-mentioned particle dispersion and by the operation of above-mentioned film drying.
The present invention described further below.
Fig. 1 is the schematic diagram of an example of the form of the film-form preparation representing the present invention.
As shown in Figure 1, in the film-form preparation of the present invention, one or more granule (hereinafter also referred to " sugar or sugar alcohol the granule ") 1a that mean diameter is in the sugar selecting free monosaccharide～six sugar of 0.1～100 μm and the group of their sugar alcohol composition is dispersed in the base material 1b containing edible polymer solvable in water and polar organic solvent and allergen (not shown).It is additionally believed that as it is shown in figure 1, in the film-form preparation of the present invention, above-mentioned sugar or sugar alcohol granule 1a are evenly dispersed in base material 1b.
The thickness of the film-form preparation of the present invention is not particularly limited, it is preferred to 30～500 μm.When thickness is less than 30 μm, from the viewpoint of film strength and the treatability of goods, it is possible to go wrong, and during more than 500 μm, the sticky sense that intraoral edible polymer brings strengthens, it is possible to feel sense of discomfort in oral cavity.
It addition, the flat shape of the film-form preparation of the present invention is not particularly limited, for instance, the arbitrary shapes such as rectangle, square, circle, ellipse can be listed.
In the film-form preparation of the present invention, as the granule of above-mentioned sugar or sugar alcohol, for instance, the granule of monosaccharide as follows, disaccharide, the sugar of three～six sugar or their sugar alcohol can be listed.As monosaccharide, for instance the aldotetrose such as erythrose, threose can be listed；The aldopentoses such as ribose, lyxose, xylose, arabinose；The aldohexoses such as allose, talose, gulose, glucose, altrose, mannose, galactose, idose；The ketotetroses such as Erythrulose；The pentulose such as xylulose, ribulose；The ketohexoses etc. such as psicose, fructose, sorbose, Tagatose.As disaccharides, for instance the α-diglucosides such as trehalose, 2-O-alpha-D-Glucopyranosyl-D-glucose., 3-O-alpha-D-Glucopyranosyl-D-glucose, maltose, dextrinose can be listed；β-the diglucosides such as isotrehalose, Chinese scholartree disaccharide, laminaribiose, cellobiose, gentiobiose；The α such as neotrehalose, β-diglucoside and lactose, sucrose, isomaltulose (palatinose) etc..As three saccharides, for instance Raffinose (raffinose) etc. can be listed.Oligosaccharide as trisaccharide～six sugar, for instance the oligosacharides cyclic etc. such as oligofructose, oligomeric galactose, oligomeric xylose, oligomeric isomaltose, oligo-chitosan (chitinoligosaccharide), oligochitosan (ChitosanOligosaccharide), glucooligosaccharides amine (oligoglucosamine), dextrin, cyclodextrin can be listed.
It addition, as the sugar alcohol of monosaccharide, for instance the tetritol such as erythritol, D-threitol, L-threitol can be listed；The pentitols such as D-R alcohol, xylitol；The hexitols such as D-iditol, galactitol (dulcitol), D-glucitol (sorbitol), mannitol；The cyclitols etc. such as inositol.It addition, as the sugar alcohol of disaccharide, for instance maltose alcohol, lactose, isomalt (hydroxyl isomaltulose, isomalt) etc. can be listed.As the sugar alcohol of oligosaccharide, tetramethylolmethane, reduction maltose malt sugar etc. can be listed.
In the film-form preparation of the present invention, above-mentioned sugar or sugar alcohol granule can be replaced, furthermore it is also possible to use a kind of or two or more mixing used.
From the film-form preparation of the present invention in the diffluent viewpoint of oral cavity content, the granule of above-mentioned sugar or sugar alcohol is preferably monosaccharide～tri-saccharide or the granule of their sugar alcohol.
It addition, allergen is albumen, peptide, it is contemplated that having the sugar of reproducibility and may pass through Maillard reaction (Maillardreaction) and significantly reduce antigenicity, therefore, the sugar of above-mentioned monosaccharide～six sugar is preferably sugar or its sugar alcohol of irreducibility.
In the film-form preparation of the present invention, as above-mentioned sugar or sugar alcohol granule, it is further preferred that trehalose that hygroscopicity is low, mannitol, xylitol, erythritol, hydroxyl isomaltulose.
Here, the sugar of monosaccharide～six sugar and their sugar alcohol have the character of essentially insoluble solution in polar organic solvent.On the other hand, owing to the film-form preparation of the present invention contains following edible polymer solvable in water and polar organic solvent, therefore, when it manufactures, it is possible to use polar organic solvent.Therefore, the film-form preparation of the present invention can with granular a large amount of containing above-mentioned sugar or sugar alcohol granule, it is possible to give the film-form preparation of the present invention with desired intensity.It addition, in conventional film-form preparation, although sometimes using organic solvent when it manufactures, but this organic solvent adds as defoamer, the bubble produced during in order to remove manufacture, not for dissolving edible polymer.
The mean diameter of above-mentioned sugar or sugar alcohol granule is 0.1～100 μm.When mean diameter is more than 100 μm, in the film-form preparation of practical thickness, flexibility is likely to become uneven according to position, it addition, uneven the tending to of particle diameter becomes big, therefore, the intensity of film-form preparation is tended to reduce (becoming fragile).On the other hand, when above-mentioned mean diameter is less than 0.1 μm, the likely coagulation of each granule, similarly, the flexibility of film-form preparation is likely to become uneven according to position.The mean diameter of above-mentioned sugar or sugar alcohol granule is more preferably 0.1～30 μm, by being set within the scope of this, within practical manufacturing process's time, it is easy to modulate the solution of these sugar and sugar alcohol even particulate dispersion.
It addition, in this manual, above-mentioned mean diameter refers to 50% mean diameter obtained with laser scattering type particle size distribution device.
As long as above-mentioned sugar or sugar alcohol granule can also be its aggregations when being in the solids in above-mentioned average particle size range, conform with context, then its shape is arbitrary.Described sugar or sugar alcohol granule can also use and carry out granulate thus above-mentioned mean diameter is in the commercially available prod of above-mentioned scope, alternatively, it is also possible to make mean diameter re-use after above-mentioned scope commercially available prod granulate.It addition, the adjustment of above-mentioned mean diameter can by utilizing the pelletize of pulverizing, dry pelletizing method, wet granulation etc., utilizing the classification etc. of sieve or grader etc. to carry out.It addition, in order to be readily available the solids in above-mentioned average particle size range, above-mentioned sugar or sugar alcohol granule are not preferably the product of recrystallization after temporarily dissolving.
In the gross weight of the film-form preparation of the present invention, the use level of above-mentioned sugar or sugar alcohol granule is preferably 1～80 weight %.When use level is lower than 1 weight %, under the thickness of practical film-form preparation, the sticky sense that following edible polymer in intraoral rapid stripping curve (dissolutionprofile), sufficient film strength, oral cavity is brought, sense of touch when touch, sometimes can't see obvious improvement, and during more than 80 weight %, if sugar or the particle diameter of sugar alcohol granule not being decreased to fairly small, it is possible to the problem such as shape retention of goods occurs.The preferred lower limit of the use level of above-mentioned sugar or sugar alcohol granule is 10 weight %, and the preferred upper limit is 60 weight %.By being set within the scope of this, under particle diameter practical on manufacturing, it is possible to improve intraoral rapid stripping curve, the sticky sense that sufficient film strength, intraoral following edible polymer bring, sense of touch when touch.
It addition, saccharide has sweet taste mostly, for being suitable the diffluent film-form preparation of oral cavity content.Certainly, as required, it is possible to add plasticizer.
Above-mentioned edible polymer solvable in water and polar organic solvent is the material of the base material of the film-form preparation constituting the present invention, as this edible polymer, be not particularly limited, if there is thin film Forming ability, there is edibility, insoluble above-mentioned sugar or sugar alcohol granule but dissolve in polar organic solvent.
It addition, in this manual, " edibility " refers to and can give by per os, allows to use on galenic pharmacy.
Here, as above-mentioned polar organic solvent, as long as dissolving above-mentioned edible polymer but insoluble above-mentioned sugar or sugar alcohol granule, for instance, it is preferred to use solubility parameter is the organic solvent of more than 9.7.As the organic solvent meeting this solubility parameter, for instance methanol, ethanol, isopropanol, propylene glycol, dichloromethane, acetone etc. can be listed.Wherein, it is preferred to use ethanol, isopropanol, dichloromethane, acetone.When the solubility parameter organic solvent lower than 9.7, sugar or sugar alcohol grain dissolution, it is possible to be difficult to disperse with graininess.
It addition, in this manual, " solubility parameter " refers to the heat of evaporation (cal/cm needed for the liquid for evaporating 1mol volume3) square root (SP value).
As above-mentioned edible polymer, specifically, it is preferred to use polyvinyl pyrrolidone (hereinafter referred to as " PVP "), hydroxypropyl cellulose (hereinafter referred to as " HPC ").From the viewpoint of sufficiently soluble water and polar organic solvent, above-mentioned PVP and HPC meets in oral cavity and to dissolve rapidly and can use polar organic solvent the two condition during fabrication.Thereby, it is possible to by dispersed with graininess to sugar undissolved in polar organic solvent or sugar alcohol granule and be carried in the base material of film-form preparation.As above-mentioned edible polymer, HPC is preferred.This is because, comparing with PVP, HPC is lower relative to the hygroscopicity of relative humidity, considers it is preferred from viewpoint in practical use.These materials can be used alone, it is also possible to is used in combination of two or more.
By controlling the thickness of the film-form preparation of the present invention, it is possible to control the dissolved in oral cavity time, by suitably adjusting the molecular weight of the edible polymers such as above-mentioned PVP, HPC, it is also possible to arbitrarily and easily control the dissolved in oral cavity time.
The molecular weight of above-mentioned PVP is preferably 2500～3,000,000, more preferably 2500～1,200,000.When the molecular weight of PVP is lower than 2500, stability and hygroscopicity are likely deteriorated, and on the contrary, during more than 3,000,000, dissolubility is likely deteriorated.
It addition, in order to be suitable to utilize the desensitization therapy of allergen, guarantee the dissolution time of film-form preparation, the molecular weight of PVP is preferably 40,000～1,200,000.
The molecular weight of above-mentioned HPC is preferably 10,000～1,150,000, more preferably 10,000～370,000.During lower than 10,000, hygroscopicity and stability are likely deteriorated, and during more than 1,150,000, dissolubility is likely deteriorated.
It addition, in order to be suitable to utilize the desensitization therapy of allergen, guarantee the dissolution time of film-form preparation, the molecular weight of HPC is preferably 30,000～370,000.
It addition, in this manual, above-mentioned molecular weight refers to weight average molecular weight, can be obtained by gel osmoticing chromatogram analysis.
The substitution value of the hydroxy propyloxy group of above-mentioned HPC is preferably more than 50.0%.Here, the assay method of the substitution value of above-mentioned hydroxy propyloxy group carries out according to the quantitative method recorded in the 15th " hydroxypropyl cellulose " item correcting each article of officina of Japan legal medical expert's medicineization.The substitution value of above-mentioned hydroxy propyloxy group is more preferably more than 53.4%.When this substitution value is lower than 50.0%, the dissolubility in water and organic solvent is likely deteriorated.
In the film-form preparation of the present invention, the use level of above-mentioned edible polymer is preferably 1～80 weight % relative to the gross weight of this film-form preparation.When this use level is lower than 1 weight %, the film-form preparation of the present invention becomes fragile, and sometimes will not show sufficient intensity, and during more than 80 weight %, be prone to the sticky sense that soluble high-molecular brings in oral cavity.The preferred lower limit of the use level of above-mentioned soluble high-molecular is 10 weight %, and the preferred upper limit is 70 weight %.
Except above-mentioned edible polymer solvable in water and polar organic solvent, as long as not interfering with in the scope of effect of the present invention, it is also possible to by appropriate only in edible polymer solvable in water or in water and organic solvent all undissolved edible polymer (also they are referred to as other edible polymer below) combination use.
As other edible polymer above-mentioned, include, for example out polyvinyl alcohol, carboxyl ethylene polymer, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylcellulose, ethyl cellulose, low degree of substitution hydroxypropyl cellulose, crystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl cellulose, the synthetic macromolecular compounds such as carboxymethyl starch sodium, sodium alginate, glucosan, casein, pulullan polysaccharide, pectin, guar gum, xanthan gum, tragacanth, acacin (acaciagum), Radix Acaciae senegalis (gumArabic), gellan gum, the macromolecular compound etc. that starch etc. are obtained by natural materials.
In this manual, about the dissolubility in water or polar organic solvent, if the amount of the water or polar organic solvent dissolving 1g solute at 20 DEG C is necessarily more than 100mL, then it is used in this solvent the statement of " insoluble ", if dissolving the water of 1g solute or the amount of polar organic solvent less than 5mL, then use the statement of " solvable ".If it addition, dissolve the water of 1g solute or the amount of polar organic solvent less than 3mL, then using the statement of " soluble ".It is also known that, the temperature of polar organic solvent is more high, and the above-mentioned sugar used in the present invention or the dissolubility of sugar alcohol granule are more low, utilize this point, it is possible to reduce the dissolubility of above-mentioned sugar or sugar alcohol granule further, it is achieved the stabilisation of graininess.
In the film-form preparation of the present invention, composition as the base material constituting this film-form preparation, in addition to those specified above, as required, it is possible to suitably use spice, correctives, sweeting agent, coloring agent, preservative, antioxidant, stabilization agent, surfactant, plasticizer (Polyethylene Glycol (PEG) etc.) etc..
Above-mentioned allergen refers to the antigen that the antibody specificity with the people suffering from anaphylactic disease is reacted.
nullSpecifically，Allergen (the Acacia farnesiana Willd. of the pollen source of trees class can be listed、Folium Et Cacumen Alni Japonicae、American ash、Fagus sylvatica、Betula、Acer palmatum、Mountain China fir (MountainCedar)、Red cypress (RedCedar)、Cottonwood (cottonwood)、Cupressaceae、American Elm、China elm、Japanese Douglas fir、Chinese sweet gum、Eucalyptus、Piao Shu、Hickory、Tilia、Acer saccharum Marsh.、Algarroba (mesquite)、Mulberry、Oak Tree、Chinese olive tree、Pecan、Pepper tree (peppertree)、Pinaster、Europe Fructus Ligustri Lucidi、Fructus Elaeagni Angustifoliae、America Firmiana platanifolia (Linn. f.) Marsili、Ailanthus altissima (mill.) swingle、Black walnut、Willow etc.)、The allergen of vegetation class pollen source is (cotton、Bermudagrass grass、English grass、Herba bromi japonici、Semen Maydis、Isodon ternifolius、Shi Mao、Wild oat、Orchardgrass、White bent、Rye grass、Oryza sativa L.、Hemerocallis citrina Baroni thatch、Timothy grass、Herba Amaranthi tricoloris、Herba chenopodii、Herba Xanthii、Radix Rumicis Japonici、Herba Solidaginis、Fructus Kochiae、Fall Herba chenopodii、Flos Inulae、Herba Urticae Cannabinae、Arisaema balansae Engl. Herba Amaranthi tricoloris (Pigwood)、Ribgrass、Ambrosia trifida、Artemisiifolia、Naked fringe pigweed、Herba Salsolae Collinae、Mountain region Artemisia、Flos Caraganae Sinicae、Sheep's sorrel (SheepSorrel) etc.)；The allergen (silkworm, flat louse, Apis, hornet, Formica fusca, Blatta seu periplaneta etc.) in worm source；Bacterium source allergen (alternaric bacteria (alterneriatenui), Aspergillus fumigatus, the pathogen of Botrytis cinerea, candidiasis, cephalosporium sp, curved spore mycete, epicoccum nigrum, acrothesium floccosum, fusarium vasinfectum belong to, compacted spore is mould, monospore branch is mould, Mucor racemosus (Mucorrasemosus), penicillium notatum, Phoma herbarum genus, yeast, rhizopus niger etc.)；The allergen (dog, cat, bird etc.) in animal chaeta source；The allergen in house moss source；The allergen etc. of food source, is not particularly limited this, as long as the antigen reacted with the antibody specificity of the people suffering from anaphylactic disease.
The use level of above-mentioned allergen according to its character etc. and different, relative to the gross weight of the film-form preparation of the present invention, be generally 1 × 10-10～60 weight %.The use level of allergen is lower than 1 × 10-10During weight %, sometimes it is unsuitable for desensitization therapy, and during more than 60 weight %, film strength significantly reduces, it is possible to the problem that the shape retention of thin film occurs.
The film-form preparation of the present invention such as can be manufactured by following method.
That is, first, use in advance pulverizing, pelletize, the grading plant etc. of appropriate amount are adjusted the above-mentioned sugar after particle diameter or sugar alcohol even particulate dispersion in the polar organic solvent of ormal weight.Then, dissolve the above-mentioned edible polymer of ormal weight wherein, further allergen is dissolved or dispersed in this solution, prepares particle dispersion.Then, the particle dispersion of the gained of appropriate amount is extended on known stripping film, form thin film, by this film drying such that it is able to manufacture the film-form preparation of the present invention.Moreover it is preferred that be required form and size by gained thin film severing, pack as required, form goods.
The method of the film-form preparation of this manufacture present invention is also a theme of the present invention.
When preparing above-mentioned particle dispersion, when producing bubble in this particle dispersion, it is possible to place a night or carry out vacuum defoamation.
As the polar organic solvent used when preparing above-mentioned particle dispersion, as long as insoluble above-mentioned sugar or sugar alcohol granule but dissolve the solvent of edible polymer.It addition, single solvent both can have been used can also to combine use solvent.Specifically, methanol, ethanol, isopropanol, propylene glycol, dichloromethane, acetone etc. can be listed.Wherein, it is preferred to use ethanol, isopropanol, dichloromethane, acetone, it is also possible to add purified water with the amount of insoluble sugar and sugar alcohol microgranule.
The effect of invention
The pain that the film-form preparation of the present invention brings also without injection, patient oneself can give allergen.It addition, by splitting, additionally it is possible to adjusting dosage, Portability is also excellent, also without dregs sense, owing to the dosage form with tablet has difference, also well prevents and wrongly takes, nursing staff's easily administration etc., it is possible to greatly improve the QOL of patient and nursing staff.
Further, since the film-form preparation of the present invention contains edible polymer solvable in water and polar organic solvent, therefore, it is possible at random control in oral cavity, the dissolution time in especially Sublingual.In a preferred embodiment, owing to can be controlled by dissolution time at 2～300 seconds, therefore the film-form preparation of the present invention is particularly suitable for adopting patient's desensitization therapy of allergen.
It addition, above-mentioned sugar or sugar alcohol granule are insoluble in polar organic solvent.Owing to the film-form preparation of the present invention uses polar organic solvent to manufacture as solvent, therefore during fabrication, above-mentioned sugar or sugar alcohol granule will not dissolve, it is possible to above-mentioned sugar or sugar alcohol granule be uniformly dispersed with graininess and be carried in the base material of film-form preparation.
And, the film-form preparation of the present invention is due to the granule of the sugar containing monosaccharide～six sugar that mean diameter is 0.1～100 μm or their sugar alcohol, therefore not only there is sufficient film strength, and the sticky sense that intraoral above-mentioned edible polymer brings can be lowered, additionally, sense of touch when touch can be improved, and be obtained in that high film strength.
And, in the manufacture method of the film-form preparation of the present invention, by using above-mentioned polar organic solvent as solvent, it is possible to low temperature, film-form preparation is dried, even the allergen of non-refractory, film-form preparation also can be manufactured under lowering the dysgenic situation to it.
Accompanying drawing explanation
Fig. 1 show the schematic diagram of an example of the form of the film-form preparation of the present invention.
Fig. 2 show the schematic diagram of the situation of viscosity persistent period test.
Description of reference numerals
1a: select at least one granule in the sugar of free monosaccharide～six sugar and the group of their sugar alcohol composition
1b: base material
2a: probe
2b: two-sided tape
2c: test film
2d: collagen film
2e: rubber
2f: testing stand
Detailed description of the invention
By following example, specifically describe the present invention, but the present invention is not restricted by the embodiments.
The sugar used in embodiment or sugar alcohol granule carry out classification by spray drying granulation, jet mill, pulverizing and utilization screening and adjust particle diameter, measure 50% mean diameter with laser scattering type particle size distribution device, as the index of the particle diameter of each microgranule.Table 1 has illustrated 50% mean diameter of the sugar used or sugar alcohol granule.
Table 1
| Sugar and sugar alcohol | 50% mean diameter [μm] |
| Mannitol microgranule | 15 7 --> |
| Mannitol particles A | 2 |
| Mannitol particles B | 33 |
| Mannitol microgranule C | 55 |
| Mannitol microgranule D | 127 |
| Lactose particles | 8 |
| Trehalose microgranule | 9 |
| Maltose microgranule | 13 |
| Xylitol microgranule | 21 |
| Glucose microgranule | 11 |
| Hydroxyl isomaltulose microgranule | 12 |
| Erythritol microgranule | 15 |
| Raffinose microgranule | 12 |
| Glucooligosaccharides amine microgranule | 17 |
| D-glucitol microgranule | 4 |
| Sucrose microgranule | 6 |
(embodiment 1)
By 67.5 weight portions control the PEARLITOL 25C microgranule of particle diameter in advance, the Polyethylene Glycol of 0.8 weight portion adds in the ethanol of 150.0 weight portions, carries out ultrasound wave dispersion.Gained material adds the weight average molecular weight about 30,000 of 64.5 weight portions, hydroxypropoxyl substitution be 53.4～77.5% HPC (HPC-SSL, Japan Cao Da system), be stirred dissolving.Add standardization allergen treatment extract " TORII " Cunninghamia lanceolata (Lamb.) Hook. pollen 2000JAU/mL (bird occupies medicine system) of 30.0 weight portions further, be stirred mixing with roller mixer (rollingmixer), prepare particle dispersion.
After abundant for this particle dispersion deaeration, polyester stripping film launches dry, manufacture the thin film of thickness about 100 μm.It is 4cm by gained thin film severing2Rectangle, it is thus achieved that film-form preparation.
(embodiment 2)
Replace, beyond ethanol, obtaining film-form preparation according to step similarly to Example 1 except with acetone.
(embodiment 3)
Except with the composition shown in table 2, obtain film-form preparation according to step similarly to Example 1.
It addition, " PVPK-30 " is the polyvinyl pyrrolidone (catalyst company of Japan system) of weight average molecular weight about 40,000 in table 2.
(embodiment 4)
Replace, beyond ethanol, obtaining film-form preparation according to step similarly to Example 3 except with acetone.
(comparative example 1)
By 67.5 weight portions control the PEARLITOL 25C microgranule of particle diameter in advance, the Polyethylene Glycol of 0.8 weight portion adds in the distilled water of 250.0 weight portions, carries out ultrasound wave dispersion.Gained material adds the pulullan polysaccharide (the former business system of woods) of 64.5 weight portions, is stirred dissolving.Add standardization allergen treatment extract " TORII " Cunninghamia lanceolata (Lamb.) Hook. pollen 2000JAU/mL (bird occupies medicine system) of 30.0 weight portions further, be stirred mixing with roller mixer (rollingmixer), prepare particle dispersion.
After abundant for this particle dispersion deaeration, polyester stripping film launches dry, manufacture the thin film of thickness about 100 μm.It is 4cm by gained thin film severing2Rectangle, it is thus achieved that film-form preparation.
(comparative example 2)
Except adopting the composition shown in table 2, obtain film-form preparation according to the step same with comparative example 1.
It addition, in table 2, " HPMC " is the hydroxymethyl cellulose (TC-5E, SHIN-ETSU HANTOTAI's chemical industry system) of weight average molecular weight about 16000.
Table 2
(embodiment 5～15)
Except adopting the composition shown in table 3, obtain film-form preparation according to step similarly to Example 1.
Table 3
(comparative example 3)
The Polyethylene Glycol of 0.8 weight portion is added in the ethanol of 220.0 weight portions, carry out ultrasound wave dispersion.Gained material adds the molecular weight about 30,000 of 132.0 weight portions, hydroxypropoxyl substitution be 53.4～77.5% HPC (HPC-SSL, Japan Cao Da system), be stirred dissolving.Add standardization allergen treatment extract " TORII " Cunninghamia lanceolata (Lamb.) Hook. pollen 2000JAU/mL (bird occupies medicine system) of 30.0 weight portions further, be stirred mixing with roller mixer, prepare solution.
After abundant for this solution deaeration, polyester stripping film launches dry, manufacture the thin film of thickness about 100 μm.It is 4cm by gained thin film severing2Rectangle, it is thus achieved that film-form preparation.
(comparative example 4)
By 67.5 weight portions control the PEARLITOL 25C microgranule of particle diameter in advance, the Polyethylene Glycol of 0.8 weight portion adds in the distilled water of 200.0 weight portions, carries out ultrasound wave dispersion.Gained material adds the molecular weight about 30,000 of 64.5 weight portions, hydroxypropoxyl substitution be 53.4～77.5% HPC (HPC-SSL, Japan Cao Da system), be stirred dissolving.Add standardization allergen treatment extract " TORII " Cunninghamia lanceolata (Lamb.) Hook. pollen 2000JAU/mL (bird occupies medicine system) of 30.0 weight portions further, be stirred mixing with roller mixer, prepare particle dispersion.
After abundant for this particle dispersion deaeration, polyester stripping film launch dry, hereafter, stripping film from this polyester stripping film, it is desirable to obtain film-form preparation, but actually owing to thin film is excessively crisp and soft, it is impossible to obtain film-form preparation.
(comparative example 5～15)
With the composition shown in table 4, according to the step same with comparative example 4, it is intended to prepare film-form preparation, but except comparative example 5,6,8 and 13, same with comparative example 4 film-form preparation can not be obtained.It is 4cm that comparative example 5,6,8 and 13 obtains severing respectively2Film-form preparation.
(comparative example 16)
The Polyethylene Glycol of 0.8 weight portion is added in the distilled water of 250.0 weight portions, carry out ultrasound wave dispersion.Gained material adds the molecular weight about 30,000 of 132.0 weight portions, hydroxypropoxyl substitution be 53.4～77.5% HPC (HPC-SSL, Japan Cao Da system), be stirred dissolving.Add standardization allergen treatment extract " TORII " Cunninghamia lanceolata (Lamb.) Hook. pollen 2000JAU/mL (bird occupies medicine system) of 30.0 weight portions further, be stirred mixing with roller mixer, prepare solution.
After abundant for this solution deaeration, polyester stripping film launches dry, manufacture the thin film of thickness about 100 μm.It is 4cm by gained thin film severing2Rectangle, it is thus achieved that film-form preparation.
Table 4
(embodiment 16)
By 67.5 weight portions control the PEARLITOL 25C microgranule of particle diameter in advance, the Polyethylene Glycol of 0.8 weight portion adds in the ethanol of 150.0 weight portions, carries out ultrasound wave dispersion.Gained material adds the molecular weight about 30,000 of 64.5 weight portions, hydroxypropoxyl substitution be 53.4～77.5% HPC (HPC-SSL, Japan Cao Da system), be stirred dissolving.Add treatment allergenic extract subcutaneous injection " TORII " Japanese red pine pollen 1: 100 (bird occupies medicine system) of 30.0 weight portions further, be stirred mixing with roller mixer, prepare particle dispersion.
After abundant for this particle dispersion deaeration, polyester stripping film launches dry, manufacture the thin film of thickness about 100 μm.It is 4cm by gained thin film severing2Rectangle, it is thus achieved that film-form preparation.
(embodiment 17～27)
nullUse treatment allergenic extract subcutaneous injection " TORII " Herba Spinaciae pollen 1: 100 (bird occupies medicine system)、Treatment allergenic extract subcutaneous injection " TORII " ragweed pollen 1: 100 (bird occupies medicine system)、Treatment allergenic extract subcutaneous injection " TORII " Fagopyrum esculentum Moench powder 1: 10 (bird occupies medicine system)、Treatment allergenic extract subcutaneous injection " TORII " silk 1: 10 (bird occupies medicine system)、Cotton 1: 10 (bird occupies medicine system) for the treatment of allergenic extract subcutaneous injection " TORII "、Treatment allergenic extract subcutaneous injection " TORII " house moss 1: 10 (bird occupies medicine system)、Treatment allergenic extract subcutaneous injection " TORII " aspergillosis 1: 1000 (bird occupies medicine system)、Treatment allergenic extract subcutaneous injection " TORII " alternaric bacteria 1: 1000 (bird occupies medicine system)、Treatment allergenic extract subcutaneous injection " TORII " candidiasis 1: 1000 (bird occupies medicine system)、Treatment allergenic extract subcutaneous injection " TORII " cladosporium (Cladosporium) 1: 1000 (bird occupies medicine system) and treatment allergenic extract subcutaneous injection " TORII " penicillium 1: 1000 (bird occupies medicine system)，With the composition shown in table 5，Thin film is prepared according to step similarly to Example 16，Obtain film-form preparation.
Table 5
(embodiment 28)
By 68.5 weight portions control the PEARLITOL 25C microgranule of particle diameter in advance, the Polyethylene Glycol of 4.0 weight portions adds in the ethanol of 130.0 weight portions, carries out ultrasound wave dispersion.Gained material adds 10.0 weight portion Japan Cunninghamia lanceolata (Lamb.) Hook. pollen (ASAHIFOOD&HEALTHCARECO., LTD manufactures), the molecular weight about 30,000 of 65.3 weight portions, hydroxypropoxyl substitution be 53.4～77.5% HPC (HPC-SSL, Japan's Cao Da system), it is stirred dissolving, prepares particle dispersion.
After abundant for this particle dispersion deaeration, polyester stripping film launches dry, manufacture the thin film of thickness about 100 μm.It is 4cm by gained thin film severing2Rectangle, it is thus achieved that film-form preparation.
(embodiment 29～31)
Use refining Cunninghamia lanceolata (Lamb.) Hook. pollen antigen Cryj1 (manufacture of woods protobiochemistry institute) and refining Cunninghamia lanceolata (Lamb.) Hook. pollen antigen Cryj2 (manufacture of woods protobiochemistry institute), with the composition shown in table 6, thin film is prepared, it is thus achieved that film-form preparation according to step similarly to Example 28.
Table 6
(embodiment 32)
By 50.0 weight portions control the PEARLITOL 25C particles A of particle diameter in advance, the Polyethylene Glycol of 1.0 weight portions adds in the ethanol of 100.0 weight portions, carries out ultrasound wave dispersion.Gained material adds the molecular weight about 30,000 of 44.0 weight portions, hydroxypropoxyl substitution be 53.4～77.5% HPC (HPC-SSL, Japan Cao Da system), be stirred dissolving.Add standardization allergen treatment extract " TORII " Cunninghamia lanceolata (Lamb.) Hook. pollen 2000JAU/mL (bird occupies medicine system) of 10.0 weight portions further, be stirred mixing with roller mixer, prepare particle dispersion.
After abundant for this solution deaeration, polyester stripping film launches dry, manufacture the thin film of thickness about 100 μm.It is 4cm by gained thin film severing2Rectangle, it is thus achieved that film-form preparation.
(embodiment 33～35)
Use the PEARLITOL 25C particles B and the PEARLITOL 25C microgranule C that control particle diameter in advance, with the composition shown in table 7, prepare thin film according to the step same with embodiment 32, it is thus achieved that film-form preparation.
(embodiment 36～39, comparative example 17)
Use the HPC (HPC-SSL that substitution value is 53.4～77.5% of molecular weight about 30,000, hydroxy propyloxy group, Japan's Cao Da system) and the HPC (HPC-L that substitution value is 53.4～77.5% of molecular weight about 140,000, hydroxy propyloxy group, Japan's Cao Da system), with the composition shown in table 7, thin film is prepared, it is thus achieved that film-form preparation according to the step same with embodiment 32.
It addition, thickness is adjusted to 250 μm by embodiment 35, thickness is adjusted to 120 μm by embodiment 36, and thickness is adjusted to 120 μm by embodiment 37, and thickness is adjusted to 120 μm by embodiment 38, and thickness is adjusted to 80 μm by embodiment 39.
Table 7
[test method]
For the intraoral stripping curve of film-form preparation of preparation, film strength, intraoral sticky sense, sense of touch when touch in each embodiment and comparative example, it is measured respectively through carrying out fissility test, dissolved in oral cavity test, the test of firm softness, tensile strength test, viscosity protracted test and sense test (sense of touch) and evaluates.It addition, for sugar scattered in film-form preparation or sugar alcohol granule, use measurement microscope particle diameter.Each test method is as follows.
(1) dissolved in oral cavity test
In the glass dish of 1000ml, add the pH6.8 phosphate buffer of 900ml, stainless steel sieve (φ 4mm) is sunk to wherein with spinning upside down, stir (300rpm) with agitator.The temperature of this solution uses constant-temperature water circulating device to control at 37 ± 2 DEG C.By test film (4cm2) sink to wherein, meanwhile, place 3cm from above2×3cm2Stainless steel wire netting (mesh size 5mm) as weight.Range estimation confirms the time terminating to test film disintegrate from the time sinking to test film, measures with stopwatch.Each sample replication 3 times, its meansigma methods is as the dissolved in oral cavity time.Apply following metewand this dissolved in oral cavity time is marked.
4:0～10 second
3:10～15 second
2:15～20 second
More than the 1:20 second
It addition, in the physical property of prepared film-form preparation, it is impossible to peel off and be then evaluated as 0.About to control the embodiment 35～39 for the purpose of dissolution time, recording actual dissolution time.
(2) tensile strength test
Use small table formula cupping machine (Shimadzu Seisakusho Ltd. manufactures, EZTEST-100M), according to " stretching test method of JISK7127 plastic sheeting and thin slice ", it is 12mm × 50mm by film-form preparation severing, as test film, after fully drying with exsiccator, test.As test speed, use 60mm/ minute.Seeing test film elongation owing to there is no, the tensile yield strength therefore mensuration obtained is as hot strength.
Each sample replication three times, its meansigma methods is hot strength.This hot strength is applied following metewand and is marked.
4:10～20N
3:5～10N
2:2～5N
1:0～2N
It addition, in the physical property of prepared film-form preparation, it is impossible to peel off and be then evaluated as 0.
(3) just softness test
This test method(s) carries out according to the test method of " JISL1096 general fabrics test method(s), 8.19 is just soft, 8.19.1A method (45 ° of cantilever methods) ".Take the test film of 5 20mm × 150mm, at one end have on the ganoid horizontal stand on inclined-plane of 45 °, place in the way of the minor face of test film with the Base alignment: See Alignment of scale.Then, by suitable method, make test film slowly slide on the direction on inclined-plane, when the central point of one end of test film contacts with inclined-plane A, read the position of the other end by scale.Length (mm) when moving with test film represents firm softness, measures surface and the back side, the mensuration of putting the cart before the horse of 5 test films respectively, calculates respective meansigma methods, obtain as firm softness.The firm softness about 50mm of the film like reagent (comparative example 3) during not add sugar considers as benchmark, and metewand sets as follows.
4:50 ± 10mm
3:50 ± 20mm
2:50 ± 30mm
1:50 ± more than 40mm
It addition, in the physical property of prepared film-form preparation, it is impossible to peel off and be then evaluated as 0.
(4) viscosity protracted test
Use flow graph (SUNSCIENTIFIC, CR-2000), test under the environment shown in Fig. 2.Use two-sided tape 2b, the test film 2c of φ 12mm is fitted on the probe 2a of φ 12mm.It addition, place rubber 2e on testing stand 2f, the collagen film 2d crossed with water retting is set thereon.Adding the purified water of 200 μ L on test film, the probe 2a of this test film 2c that makes to have fitted declines, and touches on collagen film 2d, hereafter, makes probe 2a increase.Now, by recording paper, use slide gauge, measure the viscosity persistent period after the initial tack of adhesive obtained when probe 2a departs from from collagen film 2d.Metewand is as described below.
4:0～2mm
3:2～3mm
2:3～4mm
More than 1:4mm
About from the comparative example peeling off prepared film-form preparation polyethylene terephthalate stripping film, the severing together of related stripping film, stripping film side can not being fitted on the two-sided tape of probe, similarly measuring.
(5) sense test (sense of touch)
Whether in embodiment and the film-form preparation by comparative example severing, actually draw circle 5 seconds with finger, evaluating surface is sticky sense of discomfort.Metewand is as described below.
4: without sticky sense
3: the sticky sense of not distressful degree
2: feel the sense of discomfort of sticky sample
1: very sticky, thin film remains on finger
It addition, in the physical property of prepared film-form preparation, it is impossible to peel off and be then evaluated as 0.
(6) fissility
When preparing thin film, evaluate the fissility peeled off from polyethylene terephthalate stripping film.Metewand is as described below.
4: can be easily peeled off
3: can peel off
2: can peel off reluctantly
1: can peel off reluctantly, but break
0: can not peel off completely
Table 8 has illustrated the result of the dissolved in oral cavity test of embodiment 1～15, tensile strength test, the test of firm softness, viscosity protracted test and sense test (sense of touch)；Table 9 has illustrated the result of the dissolved in oral cavity test of comparative example 1～16, tensile strength test, the test of firm softness, viscosity protracted test and sense test (sense of touch)；Table 10 has illustrated the result of the dissolved in oral cavity test of embodiment 16～27, tensile strength test, the test of firm softness, viscosity protracted test and sense test (sense of touch)；Table 11 has illustrated the result of the dissolved in oral cavity test of embodiment 28～31, tensile strength test, the test of firm softness, viscosity protracted test and sense test (sense of touch)；Table 12 has illustrated the result of the dissolved in oral cavity test of embodiment 32-34 and comparative example 17, tensile strength test, the test of firm softness, viscosity protracted test and sense test (sense of touch).Table 13 has illustrated the result of the dissolubility test of embodiment 35～39.
The evaluation of these 6 projects is added up to, is carried out the relative evaluation of example by summation score.
(7) particle diameter in measurement microscope film-form preparation is used
For embodiment 32～34, use microscope (KEYENCE
CORPORATION manufactures, THX-600) measure PEARLITOL 25C particles A～C particle diameter in the film that reality is added.Measure 200 granules, obtain their 50% mean diameter.
Table 14 illustrates the result of 50% mean diameter of the PEARLITOL 25C microgranule in the film-form preparation of embodiment 32～34 and comparative example 17.As a comparison, be also shown for the particle diameter before adding.
Table 8
As shown in table 8, the film-form preparation of embodiment 1～15 is respectively provided with good result in all assessment items, even if when coordinating various polar organic solvent, also show good evaluation result.Although it addition, the sense evaluation result of the film-form preparation of embodiment 7 is slightly worse, but in general there is good result.
(embodiment A)
Replace, beyond ethanol, manufacturing the film-form preparation of embodiment A according to step similarly to Example 1 except with dichloromethane.The film-form preparation of embodiment A is same with the film-form preparation of embodiment 1, and each evaluation result of fissility test, dissolved in oral cavity test, the test of firm softness, tensile strength test, viscosity protracted test and sense test (sense of touch) is good.
(embodiment B)
Replace, beyond ethanol, manufacturing the film-form preparation of embodiment B according to step similarly to Example 1 except with isopropanol.The film-form preparation of embodiment B is same with the film-form preparation of embodiment 1, and each evaluation result of fissility test, dissolved in oral cavity test, the test of firm softness, tensile strength test, viscosity protracted test and sense test (sense of touch) is good.
Table 9
As shown in table 9, containing the film-form preparation of the comparative example 1 of the pulullan polysaccharide of the edible polymer belonging to only solvable in water, its fissility is inferior, and the intensity of counter-bending deformation and stretching is low, confirms sticky sense.It addition, contain the film-form preparation of the comparative example 2 of the HPMC of the edible polymer belonging to only solvable in water, the intensity of its counter-bending deformation is low, confirms sticky sense.It addition, the film-form preparation of the comparative example 3 of not sugary or sugar alcohol granule, its dissolved in oral cavity is low, confirms sticky sense.It addition, the film-form preparation that HPC is dissolved in the comparative example 4～15 prepared in purified water there is no the thin film with abundant intensity.Especially, in the film-form preparation of comparative example 4,7 and 9～12, confirm a large amount of temporarily dissolve due to sugar or sugar alcohol granule after recrystallization and the crystal sugar that generates or sugar alcohol granule.In the film-form preparation of these comparative examples, the mean diameter of sugar or sugar alcohol granule is beyond 0.1～100 μ m, as a result, the intensity of film-form preparation reduces (becoming fragile).It addition, HPC is dissolved in purified water the film-form preparation of the comparative example 16 preparing, not coordinating sugar or sugar alcohol granule, it has inferior dissolved in oral cavity, confirms sticky sense.
Table 10
As shown in table 10, the film-form preparation of embodiment 16～27 is respectively provided with good result in all assessment items, even if when coordinating various allergen, also show good evaluation result.
Table 11
As shown in table 11, relative to embodiment 1, the kind that changes the Cunninghamia lanceolata (Lamb.) Hook. pollen as allergen, the embodiment 28～31 changing the composition of each composition film-form preparation in all assessment items, be respectively provided with good result.
Table 12
As shown in table 12, the film-form preparation using the embodiment 32 of the PEARLITOL 25C particles A of mean diameter 2 μm is respectively provided with good result in all assessment items, and using the mean diameter film-form preparation more than the PEARLITOL 25C particles B (mean diameter 33 μm) of PEARLITOL 25C particles A, the embodiment 33,34 of PEARLITOL 25C microgranule C (mean diameter 55 μm) respectively, its counter-bending deformation and the intensity of stretching and the result of dissolved in oral cavity are poorer than the film-form preparation of embodiment 32.
It addition, use the film-form preparation of the comparative example 17 of the PEARLITOL 25C microgranule D of mean diameter 127 μm to have the result more inferior than the film-form preparation of embodiment in fissility and intensity.
Table 13
| Embodiment | The dissolved in oral cavity time [second] |
| 35 | 176 |
| 36 | 42 |
| 37 | 28 |
| 38 | 8 |
| 39 | 4 |
As shown in table 13, using the HPC of molecular weight about 140,000 to have the dissolved in oral cavity time of 176 seconds as the film-form preparation of the embodiment 35 that soluble high-molecular, thickness are 250 μm, except thickness is 120 μm, the dissolved in oral cavity time of the film-form preparation of the embodiment 36 that other is same with embodiment 35 is 42 seconds.
It addition, use the HPC of molecular weight about 30,000 to have the dissolved in oral cavity time of 28 seconds as the film-form preparation of the embodiment 37 that soluble high-molecular, thickness are 120 μm.
In addition, use the HPC of molecular weight about 30,000 and about 140,000 to have the dissolved in oral cavity time of 8 seconds as the film-form preparation of the embodiment 38 that soluble high-molecular, thickness are 120 μm simultaneously, and except thickness is 80 μm the dissolved in oral cavity time of the film-form preparation of the embodiment 39 that other is same with embodiment 38 be 4 seconds.
To sum up, the thickness of the molecular weight and film-form preparation by adjusting soluble high-molecular, it is possible to easily control the dissolved in oral cavity time.
Table 14
As shown in table 14,50% mean diameter of the PEARLITOL 25C microgranule in the film-form preparation of embodiment 32～34 and comparative example 17 there is no change in film-form preparation and before adding, PEARLITOL 25C microgranule dissolves in film-form preparation, but disperses with the state of microgranule.
Industrial applicability
The film-form preparation containing allergen of the present invention, its sugar and sugar alcohol disperse with the state of granule, in oral cavity, especially the characteristic such as the attenuating of the sticky sense that the controllable stripping curve in Sublingual, sufficient film strength, intraoral water-soluble polymer bring, sense of touch when touch be obviously improved compared with conventional product.They are dispersed on thin film by making sugar and sugar alcohol with graininess, it is thus possible to do not damage and manufacture relevant necessary hot strength, these thin film physical property of firm softness, and only it is obviously improved dissolved in oral cavity, thin film sense of touch, intraoral sense of touch etc. and takes the characteristic of necessity.
As the solvent prepared in thin film, use the mixed liquor of purified water or purified water and polar organic solvent and during non-organic solvent, the sugar added and the grain dissolution of sugar alcohol, thin film physical property is created very big impact.In order to solve this problem, it is necessary to reduce the use level of sugar and sugar alcohol, but in the method, the match ratio of whole edible polymer polymer increases as a result, the necessary characteristic such as dissolved in oral cavity, thin film sense of touch, intraoral sense of touch is likely to decrease.And, the present invention is form and the composition of the effective film-form preparation containing allergen being enough to solve these problems.
Claims (9)
1. a film-form preparation, it is characterized in that, one or more the granule in group containing the sugar selecting free monosaccharide～six sugar that allergen, edible polymer solvable in water and polar organic solvent and mean diameter are 0.1～100 μm and their sugar alcohol composition；The thickness of described film-form preparation is 30～500 μm；
Described allergen refers to the antigen that the antibody specificity with the people suffering from anaphylactic disease is reacted,
One or more the granule that described mean diameter is in the sugar selecting free monosaccharide～six sugar of 0.1～100 μm and the group of their sugar alcohol composition does not dissolve in described polar organic solvent,
Described edible polymer solvable in water and polar organic solvent has thin film Forming ability,
One or more the granule that described mean diameter is in the sugar selecting free monosaccharide～six sugar of 0.1～100 μm and the group of their sugar alcohol composition is dispersed in described solvable in water and polar organic solvent edible polymer with graininess；
Described mean diameter is the use level in the gross weight of described film-form preparation of one or more the granule in the sugar selecting free monosaccharide～six sugar of 0.1～100 μm and the group of their sugar alcohol composition is 1～80 weight %；
The use level of described edible polymer is 1～80 weight % relative to the gross weight of described film-form preparation；
The use level of described allergen is 1 × 10 relative to the gross weight of described film-form preparation-10～60 weight %.
2. film-form preparation according to claim 1, wherein, the mean diameter of the sugar of monosaccharide～six sugar or the granule of their sugar alcohol is 0.1～30 μm.
3. film-form preparation according to claim 1 and 2, wherein, the sugar of monosaccharide～six sugar is non-reducing sugar.
4. the film-form preparation according to claim 1,2, wherein, edible polymer solvable in water and polar organic solvent is polyvinyl pyrrolidone and/or hydroxypropyl cellulose.
5. film-form preparation according to claim 3, wherein, edible polymer solvable in water and polar organic solvent is polyvinyl pyrrolidone and/or hydroxypropyl cellulose.
6. film-form preparation according to claim 4, wherein, the molecular weight of polyvinyl pyrrolidone is 2500～3,000,000.
7. film-form preparation according to claim 5, wherein, the molecular weight of polyvinyl pyrrolidone is 2500～3,000,000.
8. film-form preparation according to claim 4, wherein, the molecular weight of hydroxypropyl cellulose is 10,000～1,200,000.
9. film-form preparation according to claim 5, wherein, the molecular weight of hydroxypropyl cellulose is 10,000～1,200,000.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2010-017321 | 2010-01-28 | ||
| JP2010017321A JP5588688B2 (en) | 2010-01-28 | 2010-01-28 | Film-form preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102138914A CN102138914A (en) | 2011-08-03 |
| CN102138914B true CN102138914B (en) | 2016-07-06 |
Family
ID=43827767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110030217.3A Expired - Fee Related CN102138914B (en) | 2010-01-28 | 2011-01-26 | film-form preparation |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US8383145B2 (en) |
| EP (1) | EP2353586A1 (en) |
| JP (1) | JP5588688B2 (en) |
| KR (1) | KR20110088417A (en) |
| CN (1) | CN102138914B (en) |
| CA (1) | CA2729484A1 (en) |
| RU (1) | RU2011102923A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010086989A1 (en) | 2009-01-29 | 2010-08-05 | 日東電工株式会社 | Intraoral film-shaped base and preparation |
| JP5751868B2 (en) | 2010-03-30 | 2015-07-22 | 日東電工株式会社 | Film-form preparation and method for producing the same |
| TR201906326T4 (en) * | 2010-04-30 | 2019-05-21 | Allovate Llc | Toothpaste for allergic desensitization with oral mucosa. |
| JP5931449B2 (en) * | 2012-01-11 | 2016-06-08 | 日東電工株式会社 | Pharmaceutical composition and method for producing the same |
| JP5841433B2 (en) | 2012-01-11 | 2016-01-13 | 日東電工株式会社 | Intraoral film-form base and preparation |
| CN110505871B (en) * | 2017-03-13 | 2023-08-15 | 纳米及先进材料研发院有限公司 | High load rapidly disintegrating films for drug absorption |
| CA3105187A1 (en) | 2018-06-28 | 2020-01-02 | Arx, Llc | Dispensing method for producing dissolvable unit dose film constructs |
| JP7050734B2 (en) * | 2019-09-30 | 2022-04-08 | 鳥居薬品株式会社 | Film preparation for sublingual allergen immunotherapy |
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| CN1652824A (en) * | 2002-05-16 | 2005-08-10 | 救急药品工业株式会社 | Quickly soluble film preparations |
| CN102300565A (en) * | 2009-01-29 | 2011-12-28 | 日东电工株式会社 | Intraoral Film-like Base Agent And Formulation |
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-
2011
- 2011-01-25 KR KR1020110007261A patent/KR20110088417A/en not_active Application Discontinuation
- 2011-01-26 CN CN201110030217.3A patent/CN102138914B/en not_active Expired - Fee Related
- 2011-01-26 US US13/014,245 patent/US8383145B2/en not_active Expired - Fee Related
- 2011-01-26 CA CA2729484A patent/CA2729484A1/en not_active Abandoned
- 2011-01-26 EP EP11000618A patent/EP2353586A1/en not_active Withdrawn
- 2011-01-26 RU RU2011102923/15A patent/RU2011102923A/en not_active Application Discontinuation
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| US4687660A (en) * | 1983-08-16 | 1987-08-18 | Burroughs Wellcome Co. | Pharmaceutical delivery system |
| CN1652824A (en) * | 2002-05-16 | 2005-08-10 | 救急药品工业株式会社 | Quickly soluble film preparations |
| CN102300565A (en) * | 2009-01-29 | 2011-12-28 | 日东电工株式会社 | Intraoral Film-like Base Agent And Formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| US8383145B2 (en) | 2013-02-26 |
| JP5588688B2 (en) | 2014-09-10 |
| KR20110088417A (en) | 2011-08-03 |
| CA2729484A1 (en) | 2011-07-28 |
| EP2353586A1 (en) | 2011-08-10 |
| CN102138914A (en) | 2011-08-03 |
| JP2011153113A (en) | 2011-08-11 |
| US20110182993A1 (en) | 2011-07-28 |
| RU2011102923A (en) | 2012-08-10 |
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